The generation of the heartbeat relies on Ca-dependent Ca release (CICR) from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) channels (Bers, D. M. (2002) Nature 415:198-205). As a classical auto-catalytic signal amplification process. CICR requires robust containment mechanism(s) for the maintenance of its stability (Radwanski, P. B., et al. (2013) J Mol Cell Cardiol 58:77-83). Indeed, dysregulated RyR2-mediated Ca release manifests in spontaneous Ca oscillations resulting in life-threatening cardiac arrhythmias and cardiomyopathy (Radwanski, P. B., et al. (2013) J Mol Cell Cardiol 58:77-83; Belevych, A. E., et al. (2012) Circ Res 110:569-577; Belevych, A. E., et al. (2013) Cardiovascular research 98:240-247). These Ca-dependent cardiac diseases and disorders (“ryanopathies”) are among the leading causes of hospitalization and death in the US. The link between RyR2 dysfunction and arrhythmia is especially evident in catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia syndrome caused by mutations in RyR2 or other proteins of the RyR2 complex, including CASQ2 and CaM (Venetucci, L., et al. (2012) Nat Rev Cardiol 9:561-575). CPVT arrhythmogenesis involves aberrant spontaneous Ca release via dysregulated RyR2s (Venetucci, L., et al. (2012) Nat Rev Cardiol 9:561-575; Gyorke, S., et al. (2008) Cardiovascular research 77:245-255). This Ca elevation in turn activates Ca-dependent depolarizing currents that cause DADs and arrhythmic ectopic activity. A similar mechanism appears to account for acquired ryanopathies (i.e., atrial fibrillation, dilated/ischemic/idiopathic heart failure, ventricular arrhythmias, cardiac hypertrophy, impaired exercise capacity, sinoatrial node dysfunction, etc.) associated with abnormal posttranslational modification of RyR2 through phosphorylation and oxidation (Belevych, A. E., et al. (2013) Cardiovasc Res 98:240-247). Because of its central role in pathologic Ca signaling, RyR2 is a logical target for cardiac therapy. Indeed, pharmacological inhibition/stabilization of RyR2 (Jung, C. B., et al. (2012) EMBO Mol Med 4:180-191; Kobayashi, S., et al. (2010) Circ J 74:2579-2584; Watanabe, H., et al. (2011) Circ Res 109:712-713; Lehnart, S. E., et al. (2006) Proc Natl Acad Sci USA 103:7906-7910) (with dantrolene, flecainide and JTV519) has been reported to improve myocyte Ca handling and alleviate arrhythmia burden in preclinical and small clinical studies (Brunello, L., et al. (2013) Proc Natl Acad Sci USA 110:10312-10317; Watanabe, H., et al. (2009) Nature medicine 15:380-383; Wehrens, X. H., et al. (2004) Science 304:292-296; van der Werf, C., et al. (2011) J Am Coll Cardiol 57:2244-2254).
Despite these promising therapeutic modalities, effective and safe RyR2-based anti-arrhythmia therapies for broad application irrespective of ryanopathic etiology are lagging. This lack of progress can be attributed to several issues, most importantly: 1) lack of cardiac specificity of the promising reagents (dantrolene); 2) pro-arrhythmic adverse effects (flecainide); and 3) insufficient understanding of RyR2 regulation and Ca handling impeding the development of new therapies.
Additionally, ryanopathies in the brain and skeletal muscle due to leaky RyR has been associated with duschenne muscular dystrophy, malignant hyperthermia, seizures, cognitive disorders, diabetes, and heat stroke (Santulli G, Marks A R (2015) Current Mol Pharmac 8:206-222; Liu X et al., (2012) Cell 150:1055-1067).